"Genetic architecture of alcohol misuse candidate endophenotypes" Research Area This application addresses broad Challenge Area 03) Biomarker Discovery and Validation;specific Challenge Topic 03-AA-101,Identification of Intermediate Phenotypic Markers of Alcohol Use Disorders. The strategy of this study to explore the genetic underpinnings of a novel fMRI-based putative endophenotype for high-risk drinking in college students, by expanding the type and amount of data being collected in two existing, funded NIAAA grants, to yield a sample of 450 individuals, sufficiently powered to perform a genome-wide association study (GWAS). Dysfunctional drinking in college students significantly raises the odds for their experiencing not only alcohol-related problems in college but is also a significant risk factor for alcohol abuse and dependence a decade later. Risk markers for individuals rather than populations are lacking however. In one of the current proposals, 130 of 750 total college students assessed per year undergo structural and fMRI imaging. The current proposal has an additional 140 students per year for two years, complete an abbreviated imaging protocol, consisting of a structural sequence and fMRI during a Monetary Incentive Delay Task (MIDT) that measures the brain's response to reward and whose activation patterns we have shown are associated with alcoholism risk. We will also obtain an auditory oddball P300 event related potential assessment in all subjects undergoing imaging and derive event-related oscillation (ERO) measures from this to examine a recently published second alcohol endophenotype. Both questionnaire- and laboratory-based impulsivity measures are currently collected on all subjects;we have determined that these fall into 5 factor domains, two of which are significantly correlated with the MIDT fMRI activation patterns. Finally, DNA collection and genotyping for GWAS will be added for all study subjects. We will enrich the sample for individuals at higher risk for alcohol use disorders by choosing 30% of our subjects with a positive family history of alcohol abuse in father and at least 1 other close relative. High-risk drinking patterns, previously shown to predict later- life harmful drinking will be quantified based on several elements, derived from 6-month data on subjects'existing monthly self-reports of drinking behavior on a secure website. These include currently collected measures of quantity and frequency of drinking, plus self- reports of response to alcohol, adverse alcohol-related consequences and objective measures of college grades. Endophenotypes will be derived from the best combination of BOLD activation during the MIDT and ERO measures. Parallel independent component analysis of the fMRI and SNP data will be used to extract relations between patterns of fMRI components and SNP associations purely based on an analysis incorporating higher order statistics. The method allows for broader associations of genotypes with phenotypes than traditional hypothesis-driven univariate correlational analyses. Traditional methods requiring greater subject numbers will be used in addition. Thus, the major goal of the proposed research is to characterize the genetic architecture of two alcohol use disorder candidate endophenotypes, one novel based on abnormal responses on an fMRI monetary incentive delay task, one known and based on ERO measures, to compare these two measures to each other and to validate them against ongoing longitudinal measures the dysfunctional alcohol use. Why is a Challenge grant mechanism ideal for the proposed research? 1. Our goal of using innovative approaches to identify candidate intermediate phenotypic markers (endophenotypes) for alcoholism that are suitable for subsequent validation efforts matches the goals of this RFA and represents a new direction in the field. There are currently no reliable biomarkers for alcoholism so that the proposed search for such intermediate phenotypes that can predict disease risk is of high impact. 2. A two-year grant award is ideal for the proposed work. We can base subject recruitment for the proposed study on an ongoing large-scale NIAAA-funded research project that is already identifying subjects and characterizing them in detail for another purpose, in a manner that allows us to identify suitable individuals and obtain relevant longitudinal information, without having to build a new infrastructure to do so. We have assembled a team of investigators with unique expertise and an excellent record of effective past collaborations to pursue these studies. 3. We plan to hire and train new personnel including postdoctoral students and to employ unique genome- wide technology using US-based companies such as Illumina Inc. that will have the added benefit of stimulating the economy. The goal of this Challenge grant application is to identify a novel functional MRI-based endophenotype of alcohol misuse in subjects who are chosen from a large ongoing study of drinking in college students, to compare it with an existing electrophysiologically-based endophenotype and to determine the genetic underpinnings of these endophenotypes using a genome wide association study design. The identification of such biological markers will not only increase our knowledge of the pathophysiology of alcohol misuse, but more importantly identify individuals at high risk for the disorder.